Editing NMDA receptor (section)

=== Structure activity relationship (SAR) ===
[[File:SAR of amantadine and related compunds.jpg|thumb|right|300px|'''Figure 8:''' Structure activity relationship (SAR) of amantadine and related compounds]]

Memantine (1-amino-3,5-dimethyladamantane) is an aminoalkyl cyclohexane derivative and an atypical drug compound with non-planar, three dimensional tricyclic structure. Figure 8 shows SAR for aminoalkyl cyclohexane derivative. Memantine has several important features in its structure for its effectiveness:
* Three-ring structure with a bridgehead amine, -NH<sub>2</sub>
* The -NH<sub>2</sub> group is protonated under physiological pH of the body to carry a positive charge, -NH<sup>3+</sup>
* Two methyl (CH<sub>3</sub>) side groups which serve to prolong the dwell time and increase stability as well as affinity for the NMDA receptor channel compared with amantadine (1-adamantanamine).<ref name="Lipton1" /><ref name="Sonkusare" />

Despite the small structural difference between memantine and amantadine, two adamantane derivatives, the affinity for the binding site of NR1/NR2B subunit is much greater for memantine. In [[patch-clamp]] measurements memantine has an [[IC50|IC<sub>50</sub>]] of (2.3+0.3) μM while amantadine has an IC<sub>50</sub> of (71.0+11.1) μM.<ref name="Wanka" />
The binding site with the highest affinity is called the dominant binding site. It involves a connection between the amine group of memantine and the NR1-N161 binding pocket of the NR1/NR2B subunit. The methyl side groups play an important role in increasing the affinity to the open NMDA receptor channels and making it a much better neuroprotective drug than amantadine. The binding pockets for the methyl groups are considered to be at the NR1-A645 and NR2B-A644 of the NR1/NR2B.<ref name="Limapichat" /> The binding pockets are shown in figure 2.
Memantine binds at or near to the Mg<sup>2+</sup> site inside the NMDA receptor associated channel. The  -NH<sub>2</sub> group on memantine, which is protonated under physiological pH of the body, represents the region that binds at or near to the Mg<sup>2+</sup> site.<ref name="Lipton1" /> Adding two methyl groups to the -N on the memantine structure has shown to decrease affinity, giving an IC<sub>50</sub> value of (28.4+1.4) μM.<ref name="Wanka" />

==== Second generation derivative of memantine; nitromemantine ====
Several derivatives of Nitromemantine, a second-generation derivative of memantine, have been synthesized in order to perform a detailed [[structure activity relationship]] (SAR) of these novel drugs. One class, containing a nitro (NO<sub>2</sub>) group opposite to the bridgehead amine (NH<sub>2</sub>), showed a promising outcome. Nitromemantine utilizes memantine binding site on the NMDA receptor to target the NO<sub>x</sub> (X= 1 or 2) group for interaction with the S- nitrosylation/redox site external to the memantine binding site. Lengthening the side chains of memantine compensates for the worse drug affinity in the channel associated with the addition of the –ONO<sub>2</sub> group<ref name="Takahashi">{{cite journal | vauthors = Takahashi H, Xia P, Cui J, Talantova M, Bodhinathan K, Li W, Saleem S, Holland EA, Tong G, Piña-Crespo J, Zhang D, Nakanishi N, Larrick JW, McKercher SR, Nakamura T, Wang Y, Lipton SA | display-authors = 6 | title = Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease | journal = Scientific Reports | volume = 5 | pages = 14781 | date = October 2015 | pmid = 26477507 | pmc = 4609936 | doi = 10.1038/srep14781 | bibcode = 2015NatSR...514781T }}</ref>